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Popularized on social media, hand-moldable plastics are formed by consumers into tools, trinkets, and dental prosthetics. Despite the anticipated dermal and oral contact, manufacturers share little information with consumers about these materials, which are typically sold as microplastic-sized resin pellets. Inherent to their function, moldable plastics pose a risk of dermal and oral exposure to unknown leachable substances. We analyzed 12 moldable plastics advertised for modeling and dental applications and determined them to be polycaprolactone (PCL) or thermoplastic polyurethane (TPU). The bioactivities of the most popular brands advertised for modeling applications of each type of polymer were evaluated using a zebrafish embryo bioassay. While water-borne exposure to the TPU pellets did not affect the targeted developmental end points at any concentration tested, the PCL pellets were acutely toxic above 1 pellet/mL. The aqueous leachates of the PCL pellets demonstrated similar toxicity. Methanolic extracts from the PCL pellets were assayed for their bioactivity using the Attagene FACTORIAL platform. Of the 69 measured end points, the extracts activated nuclear receptors and transcription factors for xenobiotic metabolism (pregnane X receptor, PXR), lipid metabolism (peroxisome proliferator-activated receptor γ, PPARγ), and oxidative stress (nuclear factor erythroid 2-related factor 2, NRF2). By nontargeted high-resolution comprehensive two-dimensional gas chromatography (GC × GC-HRT), we tentatively identified several compounds in the methanolic extracts, including PCL oligomers, a phenolic antioxidant, and residues of suspected antihydrolysis and cross-linking additives. In a follow-up zebrafish embryo bioassay, because of its stated high purity, biomedical grade PCL was tested to mitigate any confounding effects due to chemical additives in the PCL pellets; it elicited comparable acute toxicity. From these orthogonal and complementary experiments, we suggest that the toxicity was due to oligomers and nanoplastics released from the PCL rather than chemical additives. These results challenge the perceived and assumed inertness of plastics and highlight their multiple sources of toxicity.

Objective: To study the relationship between serum creatine phosphokinase and outcomes of injury in victims with electrical burns., Material and Methods: Among 40 patients with electrical injury, 7 (18%) ones underwent upper limb amputation. There were 37 (92.5%) men and 3 (7.5%) women aged 37 (28; 47) years. We analyzed total serum creatine phosphokinase and MB fraction on the first day in patients with and without amputations., Results: Total serum creatine phosphokinase exceeded the upper reference value in 11 out of 33 patients without amputation and in all 7 patients with limb amputation ( p =0.001). Patients with limb amputation had significantly higher total serum creatine phosphokinase and MB fraction ( p <0.001 and p =0.030, respectively). Logistic regression equation showed that high total serum creatine phosphokinase significantly influenced amputation rate ( p <0.001), as evidenced by odds ratio (42.7, 95% CI 3.5-514.8). ROC analysis revealed the cut-off value of total serum creatine phosphokinase (950 IU/L). Sensitivity was 100% (63; 100), specificity - 94% (86; 94), positive predictive value - 78% (49; 78), negative predictive value - 100% (92; 100)., Conclusion: Total serum creatine phosphokinase depends only on severity of electrical and flame burns. Serum creatine phosphokinase is a predictor of upper limb amputation in patients with electrical injury. Total serum creatine phosphokinase ≥ 950 IU/L is significant for upper limb amputation (in CK-MB fraction within the reference values).

Environmental chemical (EC) exposures and our interactions with them has significantly increased in the recent decades. Toxicity associated biological characterization of these chemicals is challenging and inefficient, even with available high-throughput technologies. In this report, we describe a novel computational method for characterizing toxicity, associated biological perturbations and disease outcome, called the Chemo-Phenotypic Based Toxicity Measurement (CPTM). CPTM is used to quantify the EC "toxicity score" (Z ts ), which serves as a holistic metric of potential toxicity and disease outcome. CPTM quantitative toxicity is the measure of chemical features, biological phenotypic effects, and toxicokinetic properties of the ECs. For proof-of-concept, we subject ECs obtained from the Environmental Protection Agency's (EPA) database to the CPTM. We validated the CPTM toxicity predictions by correlating 'Z ts ' scores with known toxicity effects. We also confirmed the CPTM predictions with in-vitro, and in-vivo experiments. In in-vitro and zebrafish models, we showed that, mixtures of the motor oil and food additive 'Salpn' with endogenous nuclear receptor ligands such as Vitamin D3, dysregulated the nuclear receptors and key transcription pathways involved in Colorectal Cancer. Further, in a human patient derived cell organoid model, we found that a mixture of the widely used pesticides 'Tetramethrin' and 'Fenpropathrin' significantly impacts the population of patient derived pancreatic cancer cells and 3D organoid models to support rapid PDAC disease progression. The CPTM method is, to our knowledge, the first comprehensive toxico-physicochemical, and phenotypic bionetwork-based platform for efficient high-throughput screening of environmental chemical toxicity, mechanisms of action, and connection to disease outcomes., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Cognitive reserve (CR) is the ability to preserve cognitive functions in the presence of brain pathology. In the context of Alzheimer's disease (AD), patients with higher CR show better cognitive performance relative to brain damage therefore higher CR reduces the risk of dementia. There is a strong need to develop a neurophysiological biomarker of CR given the growing interest in understanding protective brain mechanisms in AD. FMRI studies indicate that frontoparietal network plays an important role in cognitive reserve. We calculated intraregional functional connectivity of lateral prefrontal cortex (FC LPFC) using functional near infrared spectroscopy (fNIRS) in the resting state of 13 healthy individuals who were also assessed for IQ and motoric skills (the Purdue Pegboard test, PPT). FC LPFC was found to positively correlate with IQ (a proxy measure of cognitive reserve) while showing a lack of or negative correlation with the PPT scores. The results demonstrate that the cost-effective, noninvasive and widely applicable fNIRS technology can be used to evaluate cognitive reserve in individuals at risk for and patients with AD with possible numerous applications in the context of healthy aging and other age-related cognitive disorders., Competing Interests: Declaration of interest None.

An approach has been developed that allows the synthesis of submicron spherical silica particles with a controlled micro-mesoporous structure possessing a large specific surface area (up to 1300 m 2 g -1 ). Particle synthesis is carried out by the hydrolysis of a mixture of various organosilanes mostly associated either with CTAB or with each other. A change in the concentration of CTAB in the reaction mixture apparently leads to a change in the formation mechanism of nuclei for the silica particle growth, which allows for varying the diameter of the synthesized particles in the range from 40-450 nm. The effect of the composition of the silica precursor ([3-(methacryloyloxy)propyl]trimethoxysilane, (3-aminopropyl)triethoxysilane and tetraethoxysilane) on the formation process and porosity of the resulting particles is studied. It was shown that by simply varying the ratio of organosilanes in the composition of the precursor, one can control the pore diameter of the particles in a wide range from 0.6-15 nm. The large-pore (up to 15 nm) silica particles are used as a matrix for the spatial distribution of luminescent carbon dots. The incorporation of carbon dots into SiO 2 particles prevents their aggregation leading to emission quenching after drying, thus allowing us to obtain highly luminescent composite particles. LEDs based on the obtained composite material show bright visible luminescence with spectral characteristics similar to that of a commercial cold white LED., (© 2021 IOP Publishing Ltd.)

A longstanding debate has surrounded the role of the motor system in speech perception, but progress in this area has been limited by tasks that only examine isolated syllables and conflate decision-making with perception. Using an adaptive task that temporally isolates perception from decision-making, we examined an EEG signature of motor activity (sensorimotor μ/beta suppression) during the perception of auditory phonemes, auditory words, audiovisual words, and environmental sounds while holding difficulty constant at two levels (Easy/Hard). Results revealed left-lateralized sensorimotor μ/beta suppression that was related to perception of speech but not environmental sounds. Audiovisual word and phoneme stimuli showed enhanced left sensorimotor μ/beta suppression for correct relative to incorrect trials, while auditory word stimuli showed enhanced suppression for incorrect trials. Our results demonstrate that motor involvement in perception is left-lateralized, is specific to speech stimuli, and it not simply the result of domain-general processes. These results provide evidence for an interactive network for speech perception in which dorsal stream motor areas are dynamically engaged during the perception of speech depending on the characteristics of the speech signal. Crucially, this motor engagement has different effects on the perceptual outcome depending on the lexicality and modality of the speech stimulus.

Environmental pollution is a threat to humans and wildlife species. Of particular concern are endocrine disrupting chemicals (EDCs). An important target of EDCs is nuclear receptors (NRs) that control endocrine and metabolic responses through transcriptional regulation. Owing in part to structural differences of NRs, adverse effects of EDCs vary significantly among species. Here, we describe a multiplexed reporter assay (the Ecotox FACTORIAL) enabling parallel assessment of compounds' effects on estrogen, androgen, thyroid, and PPARγ receptors of representative mammals, birds, reptiles, amphibians, and fish. The Ecotox FACTORIAL is a single-well assay comprising a set of species-specific, one-hybrid GAL4-NR reporter constructs transiently transfected into test cells. To harmonize cross-species assessments, we used a combination of two approaches. First, we used the same type of test cells for all reporters; second, we implemented a parallel detection of reporter RNAs. The assay demonstrated excellent quality, reproducibility, and insignificant intra-assay variability. Importantly, the EC50 values for NR ligands were consistent with those reported for conventional assays. Using the assay allowed ranking the hazard potential of environmental pollutants (e.g., bisphenols, polycyclic aromatic hydrocarbons, and synthetic progestins) across species. Furthermore, the assay permitted detecting taxa-specific effects of surface water samples. Therefore, the Ecotox FACTORIAL enables harmonized assessment of the endocrine and metabolic disrupting activity of chemicals and surface water in humans as well as in wildlife species.

Over the last two decades, the evidence has been growing that in addition to epileptic spikes high frequency oscillations (HFOs) are important biomarkers of epileptogenic tissue. New methods of artificial intelligence such as deep learning neural networks can provide additional tools for automated analysis of EEG. Here we present a Long Short-Term Memory neural network for detection of spikes, ripples and ripples-on-spikes (RonS). We used intracranial EEG (iEEG) from two independent datasets. First dataset (7 patients) was used for network training and testing. The second dataset (5 patients) was used for cross-institutional validation. 1000 events of each class (spike, RonS, ripple and baseline) were selected from the candidates initially found using a novel threshold method. Network training was performed using random selections of 50-500 events (per class) from all patients from the 1 st dataset. This 'global' network was then tested on other events for each patient from both datasets. The network was able to detect events with a good generalisability namely, with total accuracy and specificity for each class exceeding 90% in all cases, and sensitivity less than 86% in only two cases (82.5% for spikes in one patient and 81.9% for ripples in another patient). The deep learning networks can significantly accelerate the analysis of iEEG data and increase their diagnostic value which may improve surgical outcome in patients with localization-related intractable epilepsy.

While chemical analysis of contaminant mixtures remains an essential component of environmental monitoring, bioactivity-based assessments using in vitro systems increasingly are used in the detection of biological effects. Historically, in vitro assessments focused on a few biological pathways, for example, aryl hydrocarbon receptor (AhR) or estrogen receptor (ER) activities. High-throughput screening (HTS) technologies have greatly increased the number of biological targets and processes that can be rapidly assessed. Here we screened extracts of surface waters from a nationwide survey of United States streams for bioactivities associated with 69 different end points using two multiplexed HTS assays. Bioactivity of extracts from 38 streams was evaluated and compared with concentrations of over 700 analytes to identify chemicals contributing to observed effects. Eleven primary biological end points were detected. Pregnane X receptor (PXR) and AhR-mediated activities were the most commonly detected. Measured chemicals did not completely account for AhR and PXR responses. Surface waters with AhR and PXR effects were associated with low intensity, developed land cover. Likewise, elevated bioactivities frequently associated with wastewater discharges included endocrine-related end points ER and glucocorticoid receptor. These results underscore the value of bioassay-based monitoring of environmental mixtures for detecting biological effects that could not be ascertained solely through chemical analyses.

Functional near-infrared spectroscopy (fNIRS) is an optical neuroimaging technique of growing interest as a tool for investigation of cortical activity. Due to the on-head placement of optodes, artifacts arising from head motion are relatively less severe than for functional magnetic resonance imaging (fMRI). However, it is still necessary to remove motion artifacts. We present a novel motion correction procedure based on robust regression, which effectively removes baseline shift and spike artifacts without the need for any user-supplied parameters. Our simulations show that this method yields better activation detection performance than 5 other current motion correction methods. In our empirical validation on a working memory task in a sample of children 7-15 years, our method produced stronger and more extensive activation than any of the other methods tested. The new motion correction method enhances the viability of fNIRS as a functional neuroimaging modality for use in populations not amenable to fMRI., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Epilepsy is the second most prevalent neurological disorder ([Formula: see text]% prevalence) affecting [Formula: see text] million people worldwide with up to 75% from developing countries. The conventional electroencephalogram is plagued with artifacts from movements, muscles, and other sources. Tripolar concentric ring electrodes automatically attenuate muscle artifacts and provide improved signal quality. We performed basic experiments in healthy humans to show that tripolar concentric ring electrodes can indeed record the physiological alpha waves while eyes are closed. We then conducted concurrent recordings with conventional disc electrodes and tripolar concentric ring electrodes from patients with epilepsy. We found that we could detect high frequency oscillations, a marker for early seizure development and epileptogenic zone, on the scalp surface that appeared to become more narrow-band just prior to seizures. High frequency oscillations preceding seizures were present in an average of 35.5% of tripolar concentric ring electrode data channels for all the patients with epilepsy whose seizures were recorded and absent in the corresponding conventional disc electrode data. An average of 78.2% of channels that contained high frequency oscillations were within the seizure onset or irritative zones determined independently by three epileptologists based on conventional disc electrode data and videos.

Functional near-infrared spectroscopy (fNIRS) is an emerging low-cost noninvasive neuroimaging technique that measures cortical bloodflow. While fNIRS has gained interest as a potential alternative to fMRI for use with clinical and pediatric populations, it remains unclear whether fNIRS has the necessary sensitivity to serve as a replacement for fMRI. The present study set out to examine whether fNIRS has the sensitivity to detect linear changes in activation and functional connectivity in response to cognitive load, and functional connectivity changes when transitioning from a task-free resting state to a task. Sixteen young adult subjects were scanned with a continuous-wave fNIRS system during a 10-min resting-state scan followed by a letter n-back task with three load conditions. Five optical probes were placed over frontal and parietal cortices, covering bilateral dorsolateral PFC (dlPFC), bilateral ventrolateral PFC (vlPFC), frontopolar cortex (FP), and bilateral parietal cortex. Activation was found to scale linearly with working memory load in bilateral prefrontal cortex. Functional connectivity increased with increasing n-back loads for fronto-parietal, interhemispheric dlPFC, and local connections. Functional connectivity differed between the resting state scan and the n-back scan, with fronto-parietal connectivity greater during the n-back, and interhemispheric vlPFC connectivity greater during rest. These results demonstrate that fNIRS is sensitive to both cognitive load and state, suggesting that fNIRS is well-suited to explore the full complement of neuroimaging research questions and will serve as a viable alternative to fMRI.

Near-infrared spectroscopy (NIRS) is a novel technology for low-cost noninvasive brain imaging suitable for use in virtually all subject and patient populations. Numerous studies of brain functional connectivity using fMRI, and recently NIRS, suggest new tools for the assessment of cognitive functions during task performance and the resting state (RS). We analyzed functional connectivity and its possible hemispheric asymmetry measuring coherence of optical signals at low frequencies (0.01-0.1 Hz) in the prefrontal cortex in 13 right-handed (RH) and 2 left-handed (LH) healthy subjects at rest (4-8 min) using a continuous-wave NIRS instrument CW5 (TechEn, Milford, MA). Two optical probes were placed bilaterally over the inferior frontal gyrus (IFG) and the middle frontal gyrus (MFG) using anatomical landmarks of the 10-20 system. As a result, 28 optical channels (14 for each hemisphere) were recorded for changes in oxygenated (HbO) and de-oxygenated (HbR) hemoglobin. Global physiological signals (respiratory and cardiac) were removed using Principal and Independent Component Analyses. Inter-channel coherences for HbO and HbR signals were calculated using Morlet wavelets along with correlation coefficients. Connectivity matrices showed specific patterns of connectivity which was higher within each anatomical region (IFG and MFG) and between hemispheres (e.g., left IFG<->right IFG) than between IFG and MFG in the same hemisphere. Laterality indexes were calculated as t-values for the 'left>right' comparisons of intrinsic connectivity within each regional group of channels in each subject. Regardless of handedness, the group average laterality indexes were negative thus revealing significantly higher connectivity in the right hemisphere in the majority of RH subjects and in both LH subjects. The analysis of Granger causality between hemispheres has also shown a greater flow of information from the right to the left hemisphere which may point to an important role of the right hemisphere in the resting state. These data encourage further exploration of the NIRS connectivity and its application for the analysis of hemispheric relationships within the functional architecture of the brain., (Copyright © 2013 Elsevier Inc. All rights reserved.)

This paper proves the correlation between characteristics of blood flow rate in the renal veins and resistance indices of the renal arteries. As a result of polypositional assessment of venous blood flow, it was found that the violations of magistral venous blood flow in the left kidney can affect the formation and progression of varicocele, and the severity of disorders of spermatogenesis. The necessity of assessment of testicular veins and the pressure in left renal vein not only in clin- and orthostasis or Valsalva maneuver, but in the six static positions is discussed; this can allow to register the violations of magistral renal blood flow at the early stages important for fertility disorders, improve the efficiency of diagnosis and treatment of patients with varicocele.

Background: Thoracoscopic clipping of the patent ductus arteriosus is an alternative to conventional surgical closure via thoracotomy in low birth weight infants. The aim of this study is to compare of these two groups of patients for the last 11 years., Methods: We reported the data of 127 small children's who underwent standard transaxillary thoracotomy (101 patients - Group I) and video-assisted thoracoscopic surgery for patent ductus arteriosus clipping (26 patients - Group II). The two groups were compared for patients demographics, operative report and postoperative parameters., Results: The groups were similar in terms of demographics and preoperative parameters. There was significant difference in mean operative time between open and thoracoscopic procedure (44.65 min vs 38.46 min; p<0.05). Duration of care in neonatal intensive unit and length of hospital stay were significantly shorter in the Group II (16.44 d vs 8.77 d; p<0.05 and 40.13 d vs 33.65 d; p<0.05). Early complication rates were equivalent between groups (6.93% vs 3.85%; p>0.05). Rate of long-term complications was dominated in the thoracotomy group (19.80% vs 0%; p=0127)., Conclusion: Thoracoscopic ligation of the patent ductus arteriosus in infants less than 2500 g gave results better than open surgery.

Anterior and posterior brain areas are involved in the storage and retrieval of semantic representations, but it is not known how these areas dynamically interact during semantic processing. We hypothesized that long-range theta-band coherence would reflect coupling of these areas and examined the oscillatory dynamics of lexical-semantic processing using a semantic priming paradigm with a delayed letter-search task while recording subjects' EEG. Time-frequency analysis revealed facilitation of semantic processing for Related compared to Unrelated conditions, which resulted in a reduced N400 and reduced gamma power from 150 to 450ms. Moreover, we observed greater anterior-posterior theta coherence for Unrelated compared to Related conditions over the time windows 150-425ms and 600-900ms. We suggest that while gamma power reflects activation of local functional networks supporting semantic representations, theta coherence indicates dynamic coupling of anterior and posterior areas for retrieval and post-retrieval processing and possibly an interaction between semantic relatedness and working memory., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Differences in the oscillatory EEG dynamics of reading open class (OC) and closed class (CC) words have previously been found (Bastiaansen et al., 2005) and are thought to reflect differences in lexical-semantic content between these word classes. In particular, the theta-band (4-7 Hz) seems to play a prominent role in lexical-semantic retrieval. We tested whether this theta effect is robust in an older population of subjects. Additionally, we examined how the context of a word can modulate the oscillatory dynamics underlying retrieval for the two different classes of words. Older participants (mean age 55) read words presented in either syntactically correct sentences or in a scrambled order ("scrambled sentence") while their EEG was recorded. We performed time-frequency analysis to examine how power varied based on the context or class of the word. We observed larger power decreases in the alpha (8-12 Hz) band between 200-700 ms for the OC compared to CC words, but this was true only for the scrambled sentence context. We did not observe differences in theta power between these conditions. Context exerted an effect on the alpha and low beta (13-18 Hz) bands between 0 and 700 ms. These results suggest that the previously observed word class effects on theta power changes in a younger participant sample do not seem to be a robust effect in this older population. Though this is an indirect comparison between studies, it may suggest the existence of aging effects on word retrieval dynamics for different populations. Additionally, the interaction between word class and context suggests that word retrieval mechanisms interact with sentence-level comprehension mechanisms in the alpha-band.

As epilepsy remains a refractory condition in about 30% of patients with complex partial seizures, electrical stimulation of the brain has recently shown potential for additive seizure control therapy. Previously, we applied noninvasive transcranial focal stimulation via novel tripolar concentric ring electrodes (TCREs) on the scalp of rats after inducing seizures with pentylenetetrazole (PTZ). We developed a close-loop system to detect seizures and automatically trigger the stimulation and evaluated its effect on the electrographic activity recorded by TCREs in rats. In our previous work the detectors of seizure onset were based on seizure-induced changes in signal power in the frequency range up to 100 Hz, while in this preliminary study we assess the feasibility of recording high frequency oscillations (HFOs) in the range up to 300 Hz noninvasively with scalp TCREs during PTZ-induced seizures. Grand average power spectral density estimate and generalized likelihood ratio tests were used to compare power of electrographic activity at different stages of seizure development in a group of rats (n= 8). The results suggest that TCREs have the ability to record HFOs from the scalp as well as that scalp-recorded HFOs can potentially be used as features for seizure onset detection.

The behavioral responses of adult Drosophila fruit flies to a variety of sensory stimuli--light, volatile and non-volatile chemicals, temperature, humidity, gravity, and sound--have been measured by others previously. Some of those assays are rather complex; a review of them is presented in the Discussion. Our objective here has been to find out how to measure the behavior of adult Drosophila fruit flies by methods that are inexpensive and easy to carry out. These new assays have now been used here to characterize a novel mutant that fails to be attracted or repelled by a variety of sensory stimuli even though it is motile.

Epilepsy is a neurological disorder that affects approximately one percent of the world population. Anti-epileptic drugs are ineffective in 25~30% of cases. Electrical stimulation to control seizures may be an additive therapy. We applied noninvasive transcutaneous focal electrical stimulation (TFES) via concentric ring electrodes on the scalp of rats after inducing seizures with pentylenetetrazole. We found a significant increase in synchrony within the beta-gamma bands during seizures and that TFES significantly reduced the synchrony of the beta-gamma activity and increased synchrony in the delta band.

Even though recent studies have suggested that seizures do not occur suddenly and that before a seizure there is a period with an increased probability of seizure occurrence, neurophysiological mechanisms of interictal and pre-seizure states are unknown. The ability of mathematical methods to provide much more sensitive tools for the detection of subtle changes in the electrical activity of the brain gives promise that electrophysiological markers of enhanced seizure susceptibility can be found even during interictal periods when EEG of epilepsy patients often looks 'normal'. Previously, we demonstrated in animals that hippocampal and neocortical gamma-band rhythms (30-100 Hz) intensify long before seizures caused by systemic infusion of kainic acid. Other studies in recent years have also drawn attention to the fast activity (>30 Hz) as a possible marker of epileptogenic tissue. The current study quantified gamma-band activity during interictal periods and seizures in intracranial EEG (iEEG) in 5 patients implanted with subdural grids/intracranial electrodes during their pre-surgical evaluation. In all our patients, we found distinctive (abnormal) bursts of gamma activity with a 3 to 100 fold increase in power at gamma frequencies with respect to selected by clinicians, quiescent, artifact-free, 7-20 min "normal" background (interictal) iEEG epochs 1 to 14 hours prior to seizures. Increases in gamma activity were largest in those channels which later displayed the most intensive electrographic seizure discharges. Moreover, location of gamma-band bursts correlated (with high specificity, 96.4% and sensitivity, 83.8%) with seizure onset zone (SOZ) determined by clinicians. Spatial localization of interictal gamma rhythms within SOZ suggests that the persistent presence of abnormally intensified gamma rhythms in the EEG may be an important tool for focus localization and possibly a determinant of epileptogenesis.

Epilepsy affects approximately one percent of the world population. Antiepileptic drugs are ineffective in approximately 30% of patients and have side effects. We are developing a noninvasive, or minimally invasive, transcranial focal electrical stimulation (TFS) system through our novel concentric ring electrodes to control seizures. Here we report on the development of a seizure detecting algorithm to be used for automatic application of TFS. A cumulative sum (CUSUM) algorithm was evaluated that detected the electrographic seizure activity in all experiments well in advance of the behavioral seizure activity.

The notion of vascular depression (VD) includes depressive disorders resulting from organic cerebral lesions of vascular genesis. Two types of VD are distinguished: post-stroke VD (PSD) and VD proper (SDP). VD develops in case of clinically manifest (neurologic) lesions in cerebral vessels that simultaneously act as psychogenic (nosogenic) factors. SDP is associated with clinically latent vascular disorders ("silent" infarctions and white matter ischemia). VD is characterized by multiple phenomenological convergence of vascular signs and symptoms inherent in both PSD and SDP. Whatever the type of VDs, they are associated with frequent cognitive problems with a variety of dynamic patterns, viz. reversible, relatively stable, and progressing.

Near-infrared spectroscopy (NIRS) is a developing technology for low-cost noninvasive functional brain imaging. With multichannel optical instruments, it becomes possible to measure not only local changes in hemoglobin concentrations but also temporal correlations of those changes in different brain regions which gives an optical analog of functional connectivity traditionally measured by fMRI. We recorded hemodynamic activity during the Go-NoGo task from 11 right-handed subjects with probes placed bilaterally over prefrontal areas. Subjects were detecting animals as targets in natural scenes pressing a mouse button. Data were low-pass filtered<1 Hz and cardiac∕respiration∕superficial layers artifacts were removed using Independent Component Analysis. Fisher's transformed correlations of poststimulus responses (30 s) were averaged over groups of channels unilaterally in each hemisphere (intrahemispheric connectivity) and the corresponding channels between hemispheres (interhemispheric connectivity). The hemodynamic response showed task-related activation (an increase∕decrease in oxygenated∕deoxygenated hemoglobin, respectively) greater in the right versus left hemisphere. Intra- and interhemispheric functional connectivity was also significantly stronger during the task compared to baseline. Functional connectivity between the inferior and the middle frontal regions was significantly stronger in the right hemisphere. Our results demonstrate that optical methods can be used to detect transient changes in functional connectivity during rapid cognitive processes.

Near-infrared spectroscopy is a novel imaging technique potentially sensitive to both brain hemodynamics (slow signal) and neuronal activity (fast optical signal, FOS). The big challenge of measuring FOS noninvasively lies in the presumably low signal-to-noise ratio. Thus, detectability of the FOS has been controversially discussed. We present reliable detection of FOS from 11 individuals concurrently with electroencephalogram (EEG) during a Go-NoGo task. Probes were placed bilaterally over prefrontal cortex. Independent component analysis (ICA) was used for artifact removal. Correlation coefficient in the best correlated FOS-EEG ICA pairs was highly significant (p < 10(-8)), and event-related optical signal (EROS) was found in all subjects. Several EROS components were similar to the event-related potential (ERP) components. The most robust "optical N200" at t = 225 ms coincided with the N200 ERP; both signals showed significant difference between targets and nontargets, and their timing correlated with subject's reaction time. Correlation between FOS and EEG even in single trials provides further evidence that at least some FOS components "reflect" electrical brain processes directly. The data provide evidence for the early involvement of prefrontal cortex in rapid object recognition. EROS is highly localized and can provide cost-effective imaging tools for cortical mapping of cognitive processes.

Even with the latest advancements in antiepileptic drugs (AEDs) there are still many persons whose seizures are not controlled. There are also side effects reported associated with the AEDs. Electrical stimulation of the brain has shown promise toward controlling seizures. However, most brain stimulation techniques involve invasive procedures to implant electrodes and electronic stimulators. There are no conclusive descriptions of where to place the implanted electrodes to control seizures. Noninvasive electrical stimulation does not require the risks of implantation, and the electrodes can be moved easily as needed to determine where they may be the most effective in reducing seizure activity. Herein we review the progress of our group in the development of noninvasive electrical stimulation via concentric ring electrodes to control seizures in rats induced by penicillin G, pilocarpine, and pentylenetetrazole (PTZ).

The authors investigated the dependence of intraabdominal pressure on the volume of a retroperitoneal haematoma. The study included a total of thirty-four patients in whom elevation of intraabdominal pressure had solely been caused by haemorrhage into the retroperitoneal space. The volume of the retroperitoneal haematoma was calculated based on the findings of spiral computed tomography, whereas intraabdominal pressure was measured using the methods suggested by Sugrue M. and Kron I. L. The statistical analysis showed a moderate positive correlation between the retroperitoneal haematoma volume and the level of intraabdominal pressure. With the volume of the retroperitoneal haematoma approximating to 2,000 ml, intraperitoneal pressure was at the upper limit of the norm. Of the patients examined, none turned out to have developed the high intraperitoneal pressure syndrome.

By their mechanism of action local anaesthesia methods were divided into diffused and vascular. Intraosseous, intraseptal and intraligamental anesthaesias are vascular ones at capillary-venous system level. Circulatory mechanism besides effectiveness increased more than 2-fold and also promotes enhancement of cardiovascular system responses.

The beta(3)-adrenergic receptor (beta(3)AR) is an essential regulator of metabolic and endocrine functions. A major cellular and clinically significant consequence of beta(3)AR activation is the substantial elevation in interleukin-6 (IL-6) levels. Although the beta(3)AR-dependent regulation of IL-6 expression is well established, the cellular pathways underlying this regulation have not been characterized. Using a novel method of homogenous reporters, we assessed the pattern of activation of 43 transcription factors in response to the specific beta(3)AR agonist CL316243 in adipocytes, cells that exhibit the highest expression of beta(3)ARs. We observed a unique and robust activation of the CRE-response element, suggesting that IL-6 transcription is regulated via the G(s)-protein/cAMP/protein kinase A (PKA) but not nuclear factor kappa B (NF-kappaB) pathway. However, pretreatment of adipocytes with pharmacologic inhibitors of PKA pathway failed to block beta(3)AR-mediated IL-6 up-regulation. Additionally, stimulation of adipocytes with the exchange protein directly activated by cAMP (Epac) agonist did not induce IL-6 expression. Instead, the beta(3)AR-mediated transcription of IL-6 required activation of both the p38 and PKC pathways. Western blot analysis further showed that transcription factors CREB and ATF-2 but not ATF-1 were activated in a p38- and PKC-dependent manner. Collectively, our results suggest that while stimulation of the beta(3)AR leads to a specific activation of CRE-dependent transcription, there are several independent cellular pathways that converge at the level of CRE-response element activation, and in the case of IL-6 this activation is mediated by p38 and PKC but not PKA pathways.

Noninvasive recording of fast optical signals presumably reflecting neuronal activity is a challenging task because of a relatively low signal-to-noise ratio. To improve detection of those signals in rapid object recognition tasks, we used the independent component analysis (ICA) to reduce "global interference" (heartbeat and contribution of superficial layers). We recorded optical signals from the left prefrontal cortex in 10 right-handed participants with a continuous-wave instrument (DYNOT, NIRx, Brooklyn, NY). Visual stimuli were pictures of urban, landscape and seashore scenes with various vehicles as targets (target-to-non-target ratio 1:6) presented at ISI=166 ms or 250 ms. Subjects mentally counted targets. Data were filtered at 2-30 Hz and artifactual components were identified visually (for heartbeat) and using the ICA weight matrix (for superficial layers). Optical signals were restored from the ICA components with artifactual components removed and then averaged over target and non-target epochs. After ICA processing, the event-related response was detected in 70%-100% of subjects. The refined signal showed a significant decrease from baseline within 200-300 ms after targets and a slight increase after non-targets. The temporal profile of the optical signal corresponded well to the profile of a "differential ERP response", the difference between targets and non-targets which peaks at 200 ms in similar object detection tasks. These results demonstrate that the detection of fast optical responses with continuous-wave instruments can be improved through the ICA method capable to remove noise, global interference and the activity of superficial layers. Fast optical signals may provide further information on brain processing during higher-order cognitive tasks such as rapid categorization of objects.

We have developed the technique of growing amorphous a-SiO(x)(Er) films and a-SiO(x)(Er)/a-Si:H multilayer structures based on spatially separating the processes of the decomposition of an oxygen-silane gas mixture in an rf glow discharge plasma and remote magnetron sputtering of an Er target. This approach allows us to control independently the film deposition rate, the Er-ion concentration and its depth distribution in the film. Time-resolved photoluminescence measurements have shown that films and planar microcavities with an Er-doped active layer exhibit internal quantum efficiency for Er ion emission of ∼75%. The method that we suggest is a way of producing effectively emitting microcavity structures, in which the distribution profile of emission centers coincides with that of the electromagnetic field in individual layers of the structure.

The adipocyte integrates crucial information about metabolic needs in order to balance energy intake, storage, and expenditure. Whereas white adipose tissue stores energy, brown adipose tissue is a major site of energy dissipation through adaptive thermogenesis mediated by uncoupling protein 1 (UCP1) in mammals. In both white and brown adipose tissue, nuclear receptors and their coregulators, such as peroxisome proliferator-activated receptor gamma (PPARgamma) and PPARgamma coactivator 1alpha (PGC-1alpha), play key roles in regulating their development and metabolic functions. Here we show the unexpected role of liver X receptor alpha (LXRalpha) as a direct transcriptional inhibitor of beta-adrenergic receptor-mediated, cyclic AMP-dependent Ucp1 gene expression through its binding to the critical enhancer region of the Ucp1 promoter. The mechanism of inhibition involves the differential recruitment of the corepressor RIP140 to an LXRalpha binding site that overlaps with the PPARgamma/PGC-1alpha response element, resulting in the dismissal of PPARgamma. The ability of LXRalpha to dampen energy expenditure in this way provides another mechanism for maintaining a balance between energy storage and utilization.

Mustached bats emit an acoustically rich variety of calls for social communication. In the posterior primary auditory cortex, activity of neural ensembles measured as local field potentials (LFPs) can uniquely encode each call type. Here we report that LFPs recorded in response to calls contain oscillatory activity in the gamma-band frequency range (>20 Hz). The power spectrum of these high-frequency oscillations shows either two peaks of energy (at 40 Hz and 100 Hz), or just one peak at 40 Hz. The relative power of gamma-band activity in the power spectrum of a call-evoked LFP correlates significantly with the 'harmonic complexity' of a call. Gamma-band activity is attenuated with reversal of frequency-modulated calls. Amplitude modulation, even when asymmetric across call reversals, has no significant effect on gamma-band activity. These results provide the first experimental evidence that complex features within different groups of species-specific calls modify the power spectrum of evoked gamma-band activity.

Catecholamine-stimulated lipolysis is primarily a beta-adrenergic and cAMP-dependent event. In previous studies we established that the beta(3)-adrenergic receptor (beta(3)AR) in adipocytes utilizes a unique mechanism to stimulate extracellular signal-regulated kinases 1 and 2 (ERK) by direct recruitment and activation of Src kinase. Therefore, we investigated the role of the ERK pathway in adipocyte metabolism and found that the beta(3)AR agonist CL316,243 regulates lipolysis through both cAMP-dependent protein kinase (PKA) and ERK. Inhibition of PKA activity completely eliminated lipolysis at low (subnanomolar) CL316,243 concentrations and by 75-80% at higher nanomolar concentrations. The remaining 20-25% of PKA-independent lipolysis, as well as ERK activation, was abolished by inhibiting the activity of either Src (PP2 or small interfering RNA), epidermal growth factor receptor (EGFR with AG1478 or small interfering RNA), or mitogen-activated protein kinase kinase 1 or 2 (MKK1/2 with PD098059). PD098059 inhibited lipolysis by 53% in mice as well. Finally, the effect of estradiol, a reported acute activator of ERK and lipolysis, was also totally prevented by PP2, AG1478, and PD098059. These results suggest that ERK activation by beta(3)AR depends upon Src and epidermal growth factor receptor kinase activities and is responsible for the PKA-independent portion of the lipolytic response. Together these results illustrate the distinct and complementary roles for PKA and ERK in catecholamine-stimulated lipolysis.

One of the phenotypes of mice with targeted disruption of the uncoupling protein-2 gene (Ucp2-/-) is greater macrophage phagocytic activity and free radical production, resulting in a striking resistance to infectious microorganisms. In this study, the molecular mechanisms of this enhanced immune response were investigated. We found that levels of nitric oxide measured in either plasma or isolated macrophages from Ucp2-/- mice are significantly elevated in response to bacterial lipopolysaccharide challenge compared with similarly treated Ucp2+/+ mice. Likewise, expression of inducible nitric-oxide synthase and inflammatory cytokines is higher in Ucp2-/- mice in vivo and in vitro. Key steps in the activation cascade of nuclear factor (NF)-kappa B, including I kappa B kinase and nuclear translocation of NF-kappa B subunits, are all remarkably enhanced in Ucp2-/- mice, most notably even under basal conditions. The elevated basal activity of I kappa B kinase in macrophages from Ucp2-/- mice can be blocked by cell-permeable inhibitors of superoxide and hydrogen peroxide generation, but not by a specific inhibitor for inducible nitric-oxide synthase. Isolated mitochondria from Ucp2-/- cells produced more superoxide/hydrogen peroxide. We conclude that mitochrondrially derived reactive oxygen from Ucp2-/- cells constitutively activates NF-kappa B, resulting in a "primed" state to both potentiate and amplify the inflammatory response upon subsequent stimulation.

The mustached bat, Pteronotus parnellii, uses complex communication sounds ("calls") for social interactions. We recorded both event-related local field potentials (LFPs) and single/few-unit (SU) spike activity from the same electrode in the posterior region of the primary auditory cortex (AIp) during presentation of simple syllabic calls to awake bats. Temporal properties of the LFPs, which reflect activity within local neuronal clusters, and spike discharges from SUs were studied at 138 recording sites in six bats using seven variants each of 14 simple syllables presented at intensity levels of 40-90 dB SPL. There was no clear spatial selectivity to different call types within the AIp area. Rather, as shown previously, single units responded to multiple call types with similar values of the peak response rate in the peri-stimulus time histogram (PSTH). The LFPs and SUs, however, showed a rich temporal structure that was unique for each call type. Multidimensional scaling (MDS) of the averaged waveforms of call-evoked LFPs and PSTHs revealed that calls were better segregated in the two-dimensional space based on the LFP compared with the PSTH data. A representation within the "LFP-space" revealed that one of the dimensions correlated with the predominant and fundamental frequency of a call. The other dimension showed a high correlation with "harmonic complexity" ("fine" spectral structure of a call). We suggest that the temporal pattern of LFP and spiking activity reflects call-specific dynamics at any locus within the AIp area. This dynamic contributes to a distributed (population-based) representation of calls. Alternatively stated, the fundamental frequency and harmonic structure of calls, and not the recording location within the AIp, determines the temporal structure of the call-evoked LFP.

It is well established that catecholamine-stimulated thermogenesis in brown fat requires beta-adrenergic elevations in cyclic AMP (cAMP) to increase expression of the uncoupling protein 1 (UCP1) gene. However, little is known about the downstream components of the signaling cascade or the relevant transcription factor targets thereof. Here we demonstrate that cAMP- and protein kinase A-dependent activation of p38 mitogen-activated protein kinase (MAPK) in brown adipocytes is an indispensable step in the transcription of the UCP1 gene in mice. By phosphorylating activating transcription factor 2 (ATF-2) and peroxisome proliferator-activated receptor gamma (PPARgamma) coativator 1alpha (PGC-1alpha), members of two distinct nuclear factor families, p38 MAPK controls the expression of the UCP1 gene through their respective interactions with a cAMP response element and a PPAR response element that both reside within a critical enhancer motif of the UCP1 gene. Activation of ATF-2 by p38 MAPK additionally serves as the cAMP sensor that increases expression of the PGC-1alpha gene itself in brown adipose tissue. In conclusion, our findings illustrate that by orchestrating the activity of multiple transcription factors, p38 MAPK is a central mediator of the cAMP signaling mechanism of brown fat that promotes thermogenesis.

During navigation and the search phase of foraging, mustached bats emit approximately 25 ms long echolocation pulses (at 10-40 Hz) that contain multiple harmonics of a constant frequency (CF) component followed by a short (3 ms) downward frequency modulation. In the context of auditory stream segregation, therefore, bats may either perceive a coherent pulse-echo sequence (PEPE...), or segregated pulse and echo streams (P-P-P... and E-E-E...). To identify the neural mechanisms for stream segregation in bats, we developed a simple yet realistic neural network model with seven layers and 420 nodes. Our model required recurrent and lateral inhibition to enable output nodes in the network to 'latch-on' to a single tone (corresponding to a CF component in either the pulse or echo), i.e., exhibit differential suppression by the alternating two tones presented at a high rate (> 10 Hz). To test the applicability of our model to echolocation, we obtained neurophysiological data from the primary auditory cortex of awake mustached bats. Event-related potentials reliably reproduced the latching behaviour observed at output nodes in the network. Pulse as well as nontarget (clutter) echo CFs facilitated this latching. Individual single unit responses were erratic, but when summed over several recording sites, they also exhibited reliable latching behaviour even at 40 Hz. On the basis of these findings, we propose that a neural correlate of auditory stream segregation is present within localized synaptic activity in the mustached bat's auditory cortex and this mechanism may enhance the perception of echolocation sounds in the natural environment.

We present experimental and theoretical results on polarization splitting of optical resonant modes in a-Si:H/a-SiO(x):H microcavities. It is shown experimentally that the splitting sign and value can be controlled by varying the active layer thickness. The polarization splitting achieved in the microcavities is about 8 meV owing to a large optical contrast, which is the ratio of film refractive indices in the distributed Bragg reflectors. The experimental data and theoretical analysis show that the polarization splitting may be zero at a certain angle of incidence of light determined by the microcavity parameters. The measured and calculated resonant frequency values for TM and TE polarizations were used to find the optical thickness of the active layer and the stop-band center frequency of the Bragg reflector. The account of the active layer thickness fluctuations along the lateral direction provides a better fit between the experimental and theoretical spectra.

Objectives: Gamma oscillations (30-100 Hz gamma electroencephalographic (EEG) activity) correlate with high frequency synchronous rhythmic bursting in assemblies of cerebral neurons participating in aspects of consciousness. Previous studies in a kainic acid animal model of epilepsy revealed increased intensity of gamma rhythms in background EEG preceding epileptiform discharges, leading the authors to test for intensified gamma EEG in humans with epilepsy., Methods: 64 channel cortical EEG were recorded from 10 people with primary generalised epilepsy, 11 with partial epilepsy, and 20 controls during a quiescent mental state. Using standard methods of EEG analysis the strength of EEG rhythms (fast Fourier transformation) was quantified and the strengths of rhythms in the patient groups compared with with controls by unpaired t test at 1 Hz intervals from 1 Hz to 100 Hz., Results: In patients with generalised epilepsy, there was a threefold to sevenfold increase in power of gamma EEG between 30 Hz and 100 Hz (p<0.01). Analysis of three unmedicated patients with primary generalised epilepsies revealed an additional 10-fold narrow band increase of power around 35 Hz-40 Hz (p<0.0001). There were no corresponding changes in patients with partial epilepsy., Conclusions: Increased gamma EEG is probably a marker of the underlying ion channel or neurotransmitter receptor dysfunction in primary generalised epilepsies and may also be a pathophysiological prerequisite for the development of seizures. The finding provides a new diagnostic approach and also links the pathophysiology of generalised epilepsies to emerging concepts of neuronal correlates of consciousness.

Current evidence suggests that uncoupling protein-2 (UCP2) is a regulator of insulin secretion. It is also known that chronic exposure of pancreatic islets to free fatty acids (FFAs) blunts glucose-stimulated insulin secretion and is accompanied by elevated levels of UCP2. However, the mechanisms regulating expression of UCP2 in beta-cells are unknown. Here, we show that UCP2 mRNA and protein levels were increased after a 48-h exposure of INS-1(832/13) beta-cells to oleic acid (0.5 mm) by activation of the UCP2 promoter. Furthermore, progressive deletions of the mouse UCP2 promoter (from -7.3 kb to +12 bp) indicated that an enhancer region (-86/-44) was responsible for both basal and FFA-stimulated UCP2 gene transcription. This enhancer contains tightly clustered Sp1, sterol regulatory element (SRE), and double E-Box elements. While all three sequence motifs were required for basal activity of the UCP2 promoter, the mutations in either the SRE or the E-Box elements eliminated the response to FFAs. The SRE and sterol regulatory element binding protein-1 (SREBP1) appear to be crucial for the response of the UCP2 gene to FFAs, since overexpression of the nuclear forms of the SREBPs increased UCP2 promoter activity by 7-10-fold and restored the ability of E-Box mutants to respond to oleic acid. These data support a model in which SREBP is the major modulator of UCP2 gene transcription by FFA, while E-Box binding factors play a supportive role.

Perception of complex communication sounds is a major function of the auditory system. To create a coherent precept of these sounds the auditory system may instantaneously group or bind multiple harmonics within complex sounds. This perception strategy simplifies further processing of complex sounds and facilitates their meaningful integration with other sensory inputs. Based on experimental data and a realistic model, we propose that associative learning of combinations of harmonic frequencies and nonlinear facilitation of responses to those combinations, also referred to as "combination-sensitivity," are important for spectral grouping. For our model, we simulated combination sensitivity using Hebbian and associative types of synaptic plasticity in auditory neurons. We also provided a parallel tonotopic input that converges and diverges within the network. Neurons in higher-order layers of the network exhibited an emergent property of multifrequency tuning that is consistent with experimental findings. Furthermore, this network had the capacity to "recognize" the pitch or fundamental frequency of a harmonic tone complex even when the fundamental frequency itself was missing.

Fast (20-100 Hz) rhythms of electrical activity of the brain have been suggested to be important for perception and cognition providing a mechanism for temporal binding of neural activities underlying mental representations. Also, fast rhythms often precede epileptiform discharges in patients and some experimental models. Generalized slow (2-3 Hz) spike activity after systemic kainic acid (KA) in the rat has been shown to be preceded by intense gamma activity. A relationship between the intensified gamma rhythms and the subsequent spike activity was studied during kainate-induced acute epileptogenesis. Power, multiple coherence and phase were analyzed at frequencies 1-100 Hz in the EEG recorded from the hippocampal-neocortical structures of the rat. Gamma rhythms, extremely intense and highly coherent at the onset of discharges, were followed by a slow rhythm of epileptiform spikes/sharp waves. During this spike activity and immediately afterwards, the gamma power and coherence were significantly decreased. These data show an antagonism between gamma rhythms and spike activity and ability of the latter to desynchronize and suppress the former. They are supportive to the hypothesis that epileptiform spike activity may result from the extreme activation of the "anti-binding" mechanism controlling temporal binding at high frequencies. It is suggested that when fast activity is abnormally intensified, "over-binding" with global synchrony of gamma rhythms can occur in the neural networks. It may lead to inadequate synaptic modifications. To prevent this process, epileptiform discharge develops as a protective mechanism suppressing fast activity. This proposal has implications for our understanding of temporal binding in the brain and how its excessive activation may precipitate the development of pathological states., (Copyright 2002 Elsevier Science Inc.)

Interest in the biology of adipose tissue has undergone a revival in recent years with the discovery of a host of genes that contribute to the regulation of satiety and metabolic rate. The catecholamines have long been known to be key modulators of adipose tissue lipolysis and the hydrolysis of triglyceride energy stores. However, more recent efforts to understand the role of individual adrenergic receptor subtypes expressed in adipocytes and their signal transduction pathways have revealed a complexity not previously appreciated. Combined with this interest in the modulation of adipocyte metabolism is a renewed focus upon brown adipose tissue and the mechanisms of whole body thermogenesis in general. The discovery of novel homologs of the brown fat uncoupling protein (UCP) such as UCP2 and UCP3 has provoked intensive study of these mitochondrial proteins and the role that they play in fuel metabolism. The story of the novel UCPs has proven to be intriguing and still incompletely understood. Here, we review the status of adipose tissue from inert storage depot to endocrine organ, interesting signal transduction pathways triggered by beta-adrenergic receptors in adipocytes, the potential of these receptors for discriminating and coordinated metabolic regulation, and current views on the role of UCP2 and UCP3 based on physiological studies and gene knockout models.

Because of increasing evidence that G protein-coupled receptors activate multiple signaling pathways, it becomes important to determine the coordination of these pathways and their physiological significance. Here we show that the beta(3)-adrenergic receptor (beta(3)AR) stimulates p38 mitogen-activated protein kinase (p38 MAPK) via PKA in adipocytes and that cAMP-dependent transcription of the mitochondrial uncoupling protein 1 (UCP1) promoter by beta(3)AR requires p38 MAPK. The selective beta(3)AR agonist CL316,243 (CL) stimulates phosphorylation of MAP kinase kinase 3/6 and p38 MAPK in a time- and dose-dependent manner in both white and brown adipocytes. Isoproterenol and forskolin mimicked the effect of CL on p38 MAPK. In all cases activation was blocked by the specific p38 MAPK inhibitor SB202190 (SB; 1-10 microm). The involvement of PKA in beta(3)AR-dependent p38 MAPK activation was confirmed by the ability of the PKA inhibitors H89 (20 microm) and (R(p))-cAMP-S (1 mm) to block phosphorylation of p38 MAPK. Treatment of primary brown adipocytes with CL or forskolin induced the expression of UCP1 mRNA levels (6.8- +/- 0.8-fold), and this response was eliminated by PKA inhibitors and SB202190. A similar stimulation of a 3.7-kilobase UCP1 promoter by CL and forskolin was also completely inhibited by PKA inhibitors and SB202190, indicating that these effects on UCP1 expression are transcriptional. Moreover, the PKA-dependent transactivation of the UCP1 promoter, as well as its sensitivity to SB202190, was fully reproduced by a 220-nucleotide enhancer element from the UCP1 gene. We similarly observed that increased phosphorylation of ATF-2 by CL was sensitive to both H89 and SB202190, while phosphorylation of cAMP-response element-binding protein was inhibited only by H89. Together, these studies illustrate that p38 MAPK is an important downstream target of the beta-adrenergic/cAMP/PKA signaling pathway in adipocytes, and one of the functional consequences of this cascade is stimulation of UCP1 gene expression in brown adipocytes.